Development of Theoretical Methods for Studying Biological Macromolecules

新的理论技术正在发展和特点。这些工作通常与软件开发相结合，并涉及新想法的系统测试和评估。 这一发展是由当前的需求和利益驱动的。 具体项目包括：-研究复杂系统中反应机制的方法。 - 复杂构象转变的无偏强制采样和沿着反应途径的平均力潜力的估计-开发REPLICA/PATH方法，用于使用模拟退火确定复杂系统中的反应路径-开发组合的量子力学/分子建模（QM/MM）势（高斯离域MM电荷，双键原子方法）-用于QM/MM应用的GAMESS-UK和CHARMM集成-使用双键原子接口的密度泛函QM/MM-QM/MM界面交替处理的评估--使用自由能扰动和PME校正计算酸类的pK。 - 硫化物电离势的密度泛函计算-其他方法开发-RMS最佳拟合约束的开发;精确的力，相对约束-合理的药物设计：CHARMM的形状描述符设施-大分子精确相互作用能计算的开发 - 小分子/蛋白质结合能预测方法的评估-对接两个大分子的快速搜索策略的开发使用GB/SA（广义Born/表面积）技术的大分子精确相互作用能计算已经开发并应用于计算蛋白质/DNA复合物在水中的溶液中的结合能和肽-肽二聚化能。人们一直在努力改进用于模拟具有量子力学（QM）和经典力学（MM）混合的复杂系统的技术。 QM/MM方法提供了在生物系统内量子力学地处理感兴趣区域的可能性，从而允许精确表示键断裂、形成和电子转移，同时还包括来自周围经典区域的重要结构和电荷效应。 GAMESS-UK已被紧密集成到CHARMM中，以允许研究小分子和酶复合物中的催化途径。这扩展了CHARMM中的QM/MM套件，因为GAMESS-UK提供了DFT（密度泛函理论）。 经典部分电荷的高斯卷积（模糊）已经实现和测试。 这些离域电荷减少了伪影，并改善了用于处理QM/MM边界条件的双链接原子方法。该接口已被测试的一组小分子组成的一系列的烷烃，醇，胺和氨基酸，每一个与各种各样的QM方法，涉及不同程度的复杂性。 结果表明，我们的方法和实现分割成量子和分子力学区域的分子是强大的，将是非常有帮助的研究酶的机制。 A类β-内酰胺酶被用作检查反应途径的测试用例。我们还研究了一系列硫化物和二硫化物的垂直电离势使用从头算和密度泛函方法。与现有的实验数据比较表明，B3 LYP/6-311+G（d，p）水平相比，其他水平的理论产生良好的协议。建议在B3 LYP/6-311+G（d，p）水平上预测硫化物的垂直电离势，因为实验数据很难得到。

New theoretical techniques are being developed and characterized. These efforts are usually coupled with software development, and involve the systematic testing and evaluation of new ideas. This development is driven by current needs and interests. Specific projects include: - Development of methods for examining reaction mechanism in complex systems. - Unbiased forced sampling of complex conformational transitions and estimation of the potential of mean force along the reaction pathway - Development of the REPLICA/PATH method for determining reaction paths in complex systems using simulated annealing - Development of combined Quantum Mechanical/Molecular Modeling (QM/MM) potentials (Gaussian delocalize MM charges, double link atom method) - GAMESS-UK and CHARMM integration for QM/MM applications - Density functional QM/MM using a double link atom interface - Evaluation of alternate treatments of QM/MM interfaces - Calculation of pK of acids groups using Free Energy Perturbation and PME corrections. - Density functional calculations on the ionization potential of sulfides- Other method development - Development of RMS best-fit restraints; accurate forces, relative restraints - Rational drug design: shape descriptor facility for CHARMM - Development of accurate interaction energy calculations for macromolecules - Evaluation of small molecule/protein binding energy prediction methods - Development of a rapid search strategy for docking two macromolecules Accurate interaction energy calculations for macromolecules using GB/SA (Generalized Born/Surface Area) techniques have been developed and applied to calculating binding energies in solution between protein/DNA complex in water and for peptide-peptide dimerization energies. There has been a continuation of effort towards improving the techniques used to model complex systems with a mixture of quantum mechanics (QM) and classical mechanics (MM). QM/MM methods offer the possibility of treating a region of interest within a biological system quantum mechanically thereby allowing the accurate representation of bond breaking, formation, and electron transfer while also including important structural and charge effects from a surrounding classical region. GAMESS-UK has been tightly integrated into CHARMM to allow studies of catalytic paths in small molecules and enzyme complexes. This extends the QM/MM suite within CHARMM since GAMESS-UK provides DFT (Density Functional Theory). Gaussian convolution (blurring) of classical partial charges has been implemented and tested. These delocalized charges reduce artifacts and improve on the double link atom methodology for treating QM/MM boundary conditions. The interface has been tested on a set of small molecules consisting of a series of alkanes, alcohols, amines, and amino acids, each with a variety of QM methods involving different levels of sophistication. The results indicate that our method and implementation of partioning a molecule into quantum and molecular mechanics regions is robust and would be extremely helpful in studying enzyme mechanisms. A Class A beta-lactamase is being used as a test case for examination of reaction paths. We have also examined the vertical ionization potential of a series of sulfides and disulfides using ab initio and density functional methods. Comparison with available experimental data suggests that B3LYP/6-311+G(d,p) level produces excellent agreement compared to other levels of theory. We propose B3LYP/6-311+G(d,p) should be the level of choice in predicting vertical ionization potential of sulfides for which experimental data is hard to come by.